DeSylva's first successful songs were those used by Al Jolson on Broadway in the 1918 +Sinbad production, which included "I'll Say She Does". Soon thereafter he met Jolson and in 1918 the pair went to New York and DeSylva began working as a songwriter at Tin Pan Alley. In the early 1920s DeSylva frequently worked with composer George Gershwin. Together they created the experimental one-act jazz opera Blue Monday set in Harlem, which is widely regarded as a forerunner to Porgy and Bess ten years later.

In 1925, DeSylva became one third of the songwriting team with lyricist Lew Brown and composer Ray Henderson, one of the top Tin Pan Alleysongwriters of the era. The writing and publishing partnership continued until 1930, producing a string of feel-good hits and the perennial Broadway favorite Good News. The popularity of this team was so great that Gershwin's mother supposedly chided her sons for not being able to write the sort of hits turned out by the trio. The 1956 Hollywood film The Best Things in Life Are Free, starring Gordon MacRae, depicted the De Sylva, Brown and Henderson collaboration.

The Paramount all-star extravaganza Star Spangled Rhythm, which takes place at the Paramount film studio in Hollywood, features a fictional movie executive named "B.G. DeSoto" (played by Walter Abel) who is a parody of DeSylva.